Bipolar Disorders 2014 © 2014 John Wiley & Sons A/S

Published by John Wiley & Sons Ltd.

BIPOLAR DISORDERS

Review Article

Clozapine for treatment-resistant bipolar

disorder: a systematic review

a,b a,c
Li X-B, Tang Y-L, Wang C-Y, de Leon J. Clozapine for treatment- Xian-Bin Li , Yi-Lang Tang ,
a,b
resistant bipolar disorder: a systematic review. Chuan-Yue Wang and Jose
d,e,f
Bipolar Disord 2014: 00: 000–000. © 2014 John Wiley & Sons A/S. de Leon
Published by John Wiley & Sons Ltd. a
Beijing Key Laboratory of Mental Disorders,
Department of Psychiatry, Beijing Anding
Objective: To evaluate the efficacy and safety of clozapine for treatment- Hospital, Capital Medical University, bCenter of
resistant bipolar disorder (TRBD). Schizophrenia, Beijing Institute for Brain
Disorders, Laboratory of Brain Disorders (Capital
Methods: A systematic review of randomized controlled studies, open-label Medical University), Ministry of Science and
prospective studies, and retrospective studies of patients with TRBD was c
Technology, Beijing, China, Department of
carried out. Interventions included clozapine monotherapy or clozapine Psychiatry and Behavioral Sciences, Emory
combined with other medications. Outcome measures were efficacy and University School of Medicine, Atlanta, GA,
adverse drug reactions (ADRs). d
Mental Health Research Center at Eastern State
Hospital, University of Kentucky, Lexington, KY,
Results: Fifteen clinical trials with a total sample of 1,044 patients met the USA, ePsychiatry and Neurosciences Research
inclusion criteria. Clozapine monotherapy or clozapine combined with other Group (CTS-549), Institute of Neurosciences,
f
treatments for TRBD was associated with improvement in: (i) symptoms of University of Granada, Granada, Biomedical
mania, depression, rapid cycling, and psychotic symptoms, with many Research Centre in Mental Health Net
patients with TRBD achieving a remission or response; (ii) the number and (CIBERSAM), Santiago Apostol Hospital,
duration of hospitalizations, the number of psychotropic co-medications, and University of the Basque Country, Vitoria, Spain
the number of hospital visits for somatic reasons for intentional self-
harm/overdose; (iii) suicidal ideation and aggressive behavior; and (iv) doi: 10.1111/bdi.12272
social functioning. In addition, patients with TRBD showed greater clinical
improvement in long-term follow-up when compared with published Key words: bipolar disorder –
schizophrenia data. Sedation (12%), constipation (5.0%), sialorrhea (5.2%), clozapine – treatment-resistant
weight gain (4%), and body ache/pain (2%) were the commonly reported
ADRs; however, these symptoms but did not usually require drug Received 11 February 2014, revised and
discontinuation. The percentage of severe ADRs reported, such as accepted for publication 11 August 2014
leukopenia (2%), agranulocytosis (0.3%), and seizure (0.5%), appeared to be
Corresponding author:
lower than those reported in the published schizophrenia literature.
Chuan-Yue Wang, M.D., Ph.D.
Beijing Anding Hospital,
Conclusion: The limited current evidence supports the concept that Capital Medical University
clozapine may be both an effective and a relatively safe medication for No. 5 Ankang Lane
TRBD. Dewai Avenue, Xicheng District
Beijing 100088
China
Fax: +86-10-58303195
E-mail: wang.cy@163.net

Clozapine, an atypical antipsychotic, is primarily
used for the treatment of treatment-resistant
schizophrenia in most parts of the world (1, 2). Long-
term use of clozapine is associated with improvement
in clinical symptoms, measurable social and
functional gains, and decreased hospi-talization as
compared with typical antipsychotic agents (3, 4).
Furthermore, meta-analyses of
randomized clinical trials (RCTs) (5, 6) and a recent
review of effectiveness trials (7) supported the
greater efficacy of clozapine among antipsy-chotics
in schizophrenia.
A growing number of reports, however, suggest
that clozapine may also have a role in other treat-
ment-resistant psychotic conditions (8–10), such as
schizoaffective disorder and psychotic mood

Li et al.
disorders (11–13). Furthermore, case reports and
retrospective studies suggest that clozapine may be
particularly effective in the treatment of medica-tion-
resistant unipolar depression and bipolar dis-order
(BD); some even suggested it is more e ffective than
it is for schizophrenia (12, 14–16).
Compared with unipolar depression, BD is a more
serious type of mood disorder. BD is a recur-rent,
potentially disabling, sometimes even fatal
psychiatric illness (17–19), and the estimated life-
time prevalence of various types of BD is over 2.0%
(20, 21). BD is often associated with high lev-els of
unfavorable outcomes or treatment resis-tance (22–
24). In contrast to schizophrenia, definitions of
treatment-resistant bipolar disorder (TRBD) vary
greatly (17, 25–27). However, a fail-ure to respond to
at least two trials of dissimilar treatments, involving
an adequate dose and dura-tion, could serve as a
conservative definition (28–31).
Although mood disorder was traditionally con-
sidered a rather rare condition in China, recently
conducted epidemiological studies in the country
showed that it is one of the common mental disor-
ders (32, 33), with a one-month prevalence of 6.1%
(32). Unlike other countries, clozapine has been
widely used for BD in China despite not having been
approved for mood disorders (34–36), and it is
indeed one of the most commonly used antipsy-
chotics in the treatment of BD (34, 37, 38). Some
psychiatrists even preferred it as a first-line treat-
ment for mania (38–40). Similar to findings from
studies in Western countries, RCTs showed that
clozapine was an effective add-on treatment to an-
tidepressants for treatment-resistant depression (41).
Clozapine was also effective for treatment-resistant
mania in a case report (42) and an RCT (43).
Clozapine is a drug of choice for TRBD in China
but the evidence for its use in Western coun-tries
remains sparse, and the studies are limited to case
reports (44), open-label trials (11), and only one RCT
with fewer than 20 patients in each group (45). As
China has the largest population on cloza-pine (46–
48), the Chinese experience and studies may be of
keen interest to Western psychiatrists (49). So far, no
exhaustive systematic review on clozapine for TRBD
has been published.
The primary aim of this review was to evaluate the
efficacy and safety of clozapine for TRBD. As
previously mentioned, in addition to international
databases, we also included Chinese databases that
are not usually reviewed in articles written by
Western psychiatrists. Particular attention was paid to
safety and tolerability, as the potentially severe
adverse drug reactions (ADRs) associated
with clozapine are commonly a factor discouraging
clinicians from prescribing it.
Methods
Before we conducted this systematic review, our
protocol of reviewing clozapine use for TRBD was
published online (http://www.crd.york.ac.uk/
prospero/); the registration number was
CRD42013004322 at the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses
(PRISMA). PRISMA provides an evidence-based
minimum set of items for reporting in systematic
reviews and meta-analyses (50).
Types of studies
All types of trials evaluating the efficacy and safety
of clozapine for TRBD were eligible for inclusion.
We included RCTs (Table 1), open-label retrospec-
tive studies (Table 2), and prospective trials (Table 3).
We excluded meta-analyses and system-atic reviews.
We also excluded from the compre-hensive review
case series and reports, since they offer a lower level
of evidence, and are associated with a high suspicion
of publication biases. How-ever, we have included
them in Table 4 and pro-vided a brief statement on
them for the sake of entirety. The retrospective open
study by Nielsen et al. (51) was included in this
review (Table 2), although the sample also included
patients with non-TRBD; it was not possible to
exclude them. All tables provided details of the
contamination of the studies by other diagnoses when
it was not pos-sible to separate the patients.
Study selection
We searched PubMed, Embase, and Cochrane
Library databases and the Cochrane Controlled Trials
Register of clozapine for TRBD. We also searched
the Chinese databases [the Chinese Bio-medical
Literature and China National Knowledge
Infrastructure databases] using the same keywords.
The search included all studies published between
January 1979 and June 2014, regardless of lan-guage.
The keywords used for the searches included:
clozapine, bipolar disorder, manic, depres-sion,
resistant/resistance/refractory, drug therapy, and trial.
The keywords were used in combination with the
Boolean operators AND, OR, and NOT. We
supplemented the search by using the ‘related article’
function. We also manually searched bibli-ographies
of RCTs, meta-analyses, and systematic reviews for
studies that were missed in the initial electronic
search (52).
 Clozapine for treatment-resistant bipolar disorder

Table 1. Clozapine randomized controlled trials for treatment-resistant bipolar disorder (TRBD)
Suppes et al. 1999 (45)
Population: 38 patients meeting the DSM-IV criteria for BD (n = 26) or SAD (n = 12) who were deemed treatment-resistant [failure
of adequate treatment with two mood stabilizers (lithium, valproate, or carbamazepine) at standard therapeutic levels]. Subjects
were randomly assigned to clozapine add-on treatment (n = 19) or TAU (no clozapine) (n = 19)
Intervention: Clozapine (355 mg/day) add-on therapy
Comparison: TAU
Measures: Patients received monthly ratings on the BPRS, CGI, BRMS, HDRS, SAPS, SANS and AIMS, and a 40-item side-
effect checklist
Study design: Randomized, TAU-controlled study with follow-up of one year
a
Results : Significant between-group differences were found in scores on all rating scales except the HDRS. Total medication use over
one year significantly decreased in the clozapine group. No significant differences in physical complaints between groups were noted
Tan 2010 (43)
Population: 71 patients with DSM-IV BD who were classified as having TRBD were randomly assigned to clozapine added to
lithium treatment (n = 35) or clozapine added to valproate treatment (n = 36). Treatment resistance was defined as failure of
adequate treatment with two different antidepressants
Intervention: Clozapine (100–300 mg/day) added to lithium (500–1,500 mg/day)
Comparisons: Clozapine (100–300 mg/day) added to valproate (600–1,800 mg/day)
Measures: Patients received ratings on BPRS, HDRS, and TESS at Weeks 0, 1, 2, 4, and 6
Study design: Randomized, open-controlled study
a
Results : In the study group, 89% of patients were responders (based on BPRS and HDRS) to clozapine added to lithium compared
with 64% of patients receiving clozapine added to valproate (p < 0.05). No significant differences in adverse drug reactions between
the groups were found

AIMS = Abnormal Involuntary Movement Scale; BPRS = Brief Psychiatric Rating Scale; BRMS = Bech–Rafaelsen Mania Scale; CGI =
Clinical Global Impression; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HDRS = Hamilton Depression
Rating Scale; SAD = schizoaffective disorder; SANS = Scale for the Assessment of Negative Symptoms; SAPS = Scale for the
Assessment of Positive Symptoms; TAU = treatment-as-usual; TESS = Treatment Emergent Symptom Scale.
a
Clinical remission and response were defined differently in each study.

One author (X-BL) independently inspected
citations from the searches and identified relevant
abstracts. A random 20% of the samples were
independently re-inspected by author Y-LT to ensure
reliability. When disagreements arose, the
full report was acquired for more detailed scrutiny.
Full reports of the abstracts meeting the review
criteria were obtained and inspected by X-BL. Again,
a random 20% of reports were re-inspected by Y-LT
in order to ensure reliable selection.
Table 2. Clozapine retrospective studies for treatment-resistant bipolar disorder (TRBD)
McElroy et al. 1991 (12)
Sample: All patients were either inadequately responsive to or unable to tolerate standard biological therapies
Methods: Survey of treating clinicians and chart data for all 85 consecutive patients, including 39 with schizophrenia, 25 with SAD,
and 14 with psychotic BD, who received clozapine for at least six weeks at one center
Results: Compared to patients with schizophrenia, patients with SAD and psychotic BD had significantly higher response rates to
clozapine (10% for schizophrenia versus 15–20% for SAD and 43% for psychotic BD)
Chang et al. 2006 (58)
Sample: Patients with BD resistant to conventional treatment
Methods: Analysis of clinical data from medical records of 51 patients with DSM-IV BD treated with add-on clozapine for >6 months
Results: The number of hospital days/year was reduced in 90% of patients after clozapine add-on treatment. The total number and
duration of hospitalizations/year also decreased. Significant reductions were found in the number and duration of hospitalizations
associated with manic, depressive, and hypomanic episodes. Long-term efficacy of clozapine add-on was supported by continuous
decreases in hospital days/year in the 27 selected patients
Nielsen et al. 2012 (51)
Sample: A total of 21,473 patients with a lifetime diagnosis of ICD-10 BD, of whom only 326 (1.5%) were treated with clozapine
and were included in a mirror-image analysis
Methods: A pharmacy-epidemiologic database study was carried out in Denmark, investigating the effectiveness of clozapine in
patients with BD (without a schizophrenia-spectrum disorder), between 1996 and 2007, using a two-year mirror-image design
Results: Clozapine appeared to be an appropriate choice for TRBD. Compared to the pre-clozapine period, during clozapine
treatment, the mean number of bed-days decreased from 179 to 35. The mean number of admissions was reduced from 3.2 to 2.0.
Overall, 240 patients (74%) had reduced bed-days and 130 (40%) were not admitted while treated with clozapine. Moreover, the
number of psychotropic co-medications was reduced from 4.5 DDD (25–75 percentiles: 2.4–8.2) to 3.9 DDD (25–75 percentiles:
2.4–6.1). The percentage of patients with hospital visits for intentional self-harm/overdose was reduced significantly from 8% to 3%

BD = bipolar disorder; DDD = defined daily doses; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; ICD-10
= International Classification of Diseases, 10th edition; SAD = schizoaffective disorder.
4

Asse
ssme
Table 3. Clozapine open-label trials for treatment-resistant bipolar disorder nt of
Funct
Resistance definition Treatments Duration ionin
Study Subjects (failure of) (mg/day) (months) g;
HDR
Suppes et al. 7 with dysphoric Standard CLZ (50–500) + 36–60 Symptomatic and S functional
= improve
1992 (16) mania treatments ACs patients sustained
Hamisubstantial gain
including ACs up over 3 years. No further hospita
lton
7 patients Depr
Banov et al. 52 BD, 81 SAD, Undefined CLZ 18.7 BD manic and SAD essiobipolar patients
1994 (11) 14 UD, 40 SCH than UD, BD, andn SAD depressed
significantly greater
Ratin improvement in
One or more episodes
g of depressio
DiscontinuationScale
Kimmel et al. 25 manic with Li, ACs, and CLZ 13 18 of 25 patients; demonstrated
Li = a>
1994 (62) BD or SAD ≥2 APs, or intolerant
Kowatch et al. 5 children or Multiple trials of APs CLZ (75–225) + 2 There was a 42% decrease in the C
1995 (65) adolescents and ACs, or intolerance Li behavior and psychotic symptoms
with BD
Zarate et al. 17 mood Combinations of Li, CLZ 16.1 65% (11/17) had no subsequent re-h
1995 (61) disorders ACs, APs, and ECT; Significant improvement in CGI sco
or had tardive dyskinesia
Calabrese et al. 25 acutely manic Li, ACs, and APs, CLZ (494) 4 72% (18/25) improved on the YMRS
1996 (44) intolerable ADRs, or both The patients with BD as compared
rapid cycling patients as compared
greater improvement in total BPRS
Green et al. 22 active manic 500 mg/day of chlorpromazine CLZ 3 57% (13/22) improved on the BPRS
2000 (63) or its equivalent and (8/22) on the CGI, and 77% (17/22
Li of at least 6 weeks reduction on all three scales
Ciapparelli et al. 34 psychotic BD, Adequate treatment with CLZ flexible 24 All patients showed significant impro
2000 (59) 31 SCH, 26 SAD, 3 different classes of APs doses on BPRS and CGI). The presence
bipolar type greater improvement at endpoint
Ciapparelli et al. 37 psychotic BD, Adequate treatment with CLZ flexible 48 Patients with SAD and BD show gre
2003 (60) 34 SCH, 30 SAD, 3 different classes of APs doses with SCH. Patients with BD had the
bipolar type highest psychosocial and occupatio
on BPRS, CGI, and GAF)
Fehr et al. 9 BD 2 ACs + APs CLZ (156 77) 12 Three patients demonstrated striking
2005 (64) previous levels of functioning (base
had moderate improvement in moo
on BPRS and HDRS), and one pat

AC = anticonvulsant; ADR = adverse drug reaction; AP = antipsychotic; BD = bipolar disorder; BPRS = Brief Psychiatric
Rating Scale; CGI = Clinical Global Impression; CLZ = clozapine; ECT = electroconvulsive therapy; GAF = Global
 Li et al.
lithium; SAD = schizoaffective disorder; SCH = schizophrenia; UD = unipolar depression; YMRS = Young Mania Rating
Scale.
 Clozapine for treatment-resistant bipolar disorder

Table 4. Clozapine case series and reports for treatment-resistant bipolar disorder

Resistance
definition Treatments Duration
Study Subjects Age, gender (failure of) (mg/day) (months) Main findings

Calabrese et al. 2 RC BD 47 years, F AC + AP CLZ (250–350) 1.5–3.5 Remission

1991 (74) 48 years, F
Suppes et al. 3 RC BD 43 years, F AP + AC CLZ (150–400) + Li 12–20 2 remission,
1994 (15) 25 years, F 1 response
45 years, F
Antonacci & 4 euphoric Unavailable Standard CLZ _ Enhanced functioning
Swartz mania treatments + AC and insight
1995 (70)
Poyurovsky & 2 mania 24 years, M AP + AC CLZ (250–350) _ Remission
Weizman 41 years, F + ECT
1996 (71)
Lancon & Llorca 1 RC BD 42 years, F Conventional CLZ _ Successfully treated
1996 (75) therapy
Mahmood et al. 3 mania Unavailable AP + AC CLZ _ Successfully treated
1997 (72)
Chanpattana 1 mania 26 years, M Conventional CLZ (200) + ECT 18 Complete remission
2000 (73) treatment
Xu 2003 (42) 1 mania 40 years, F AP + AC CLZ (600) + 1 Remarkably effective
Li (1,500) +
CBZ (600)
Chen et al. 1 RC BD 38 years, F Various biological CLZ (350) + 36 Complete remission
2005 (76) therapies TPR (300)
Vijay Sagar 1 juvenile- 18 years, F AC combinations CLZ (200) 24 Remission
2005 (79) onset BD
Quante et al. 3 BD, 2 UD Not provided Medications + CLZ (125 and 375) 12 4/5 patients showed
2007 (119) ECT steady improvement
Gupta 1 BD 28 years, M Standard AC CLZ (350) 66 No hospitalization and
2009 (78) no more episodes
Bastiampillai 1 RC BD 52 years, F Standard APs + CLZ (150) + 60 Sustained remission
et al. 2010 (77) ACs LTG (100)
Bennedetti et al. 7 SAD and Three patients, mean Treatment Aripiprazole (6.8) + – Remission
2010 (29) psychotic BD 36 years, M resistant CLZ (293)
Four patients, mean
40 years, F

AC = anticonvulsant; AP = antipsychotic; BD = bipolar disorder; CBZ = carbamazepine; CLZ = clozapine; ECT = electroconvulsive
therapy; F = female; Li = lithium; LTG = lamotrigine; M = male; RC = rapid cycling; SAD = schizoaffective disorder; TPR = topiramate;
UD = unipolar depression.

Where it was not possible to resolve disagreement by
discussion, a third author (C-YW) mediated the
decision. If the matter was unresolved, an attempt
was made to contact the authors of the original study
for clarification (53).
Data extraction
Review authors X-BL and Y-LT considered all
included studies initially, without seeing compari-son
data, to judge clinical, methodological and sta-tistical
heterogeneity and thereby decide whether each study
would be included for meta-analysis or other data
synthesis. We then extracted data into standard,
simple forms. X-BL extracted data from all included
studies. In addition, to ensure reliabil-ity, Y-LT
independently extracted data from a ran-dom sample
of these studies, comprising 30% of
the total. Again, any disagreement was discussed,
decisions were documented, and, if necessary, authors
of studies were contacted for clarification. Data
presented only in graphs and figures were extracted
whenever possible, but included only if two authors
independently had the same result. We also attempted
to contact authors through an open-ended request in
order to obtain missing information or for
clarification whenever deemed necessary. If studies
were multi-center, we extracted data relevant to each
component center separately (53).
Assessment of reporting biases
Reporting biases arise when the dissemination of
research findings is influenced by the nature and
direction of results. We tried to locate the research

Li et al. protocols of included RCTs. If the protocol was

available, outcomes in the protocol and in the
published report were compared. If the protocol was
not available, outcomes listed in the methods section
of the trial report were compared with the actually
reported results (54).
Grading recommendations
We used the grading of recommendations assess-
ment, development, and evaluation (GRADE) sys-
tem to rate the quality of evidence and strength of
recommendations of this systematic review follow-
ing the guidelines of the Cochrane Collaboration.
GRADE included systematic assessments of all
included trials across six main domains for each
outcome: limitations of the study design and exe-
cution, inconsistency, indirectness, imprecision of
results, publication bias, and large treatment effect.
Accordingly, we graded the recommendation for the
outcome measure of clozapine for BD as very low,
low, moderate, or high (Table 5).
Results
The various combinations of the search ‘clozapine,
bipolar disorder, manic, depression, resistant or
resistance, refractory’ yielded 342 articles, of which
15 studies met the criteria. In total, 1,044 patients
with TRBD had received clozapine treatment (Fig. 1).
There were two RCTs (Table 1); three ret-
rospective studies (Table 2), and 10 open-label
prospective trials (Table 3). These studies were
equally distributed across the years between 1991 and
2012, which indicates that clozapine for TRBD has
been a rather long-lasting, clinically important topic
for the last 25 years.
It was not possible to conduct a meta-analysis
because of the study’s heterogeneity, including dif-
ferences in illness phase (mania, depression, or rapid
cycling BD), methodology (open-label trial or RCT)
and outcome definition (response or remission).
Although meta-analysis is a powerful tool for
analyzing data (55), confounding inter-study
variables that cannot be controlled may vio-late basic
statistical assumptions, making this type of analysis
error-prone (56, 57). Therefore, we only extracted
data onto standard, simple forms on a case-by-case
basis and reported the efficacy of clozapine for
TRBD when available, as well as other descriptive
statistics. Compared with effi-cacy, there was less
heterogeneity in ADRs. There-fore, we conducted
data synthesis using this term, and all trials with ADR
details were included; the percentage of each ADR
was computed in this review and is presented in Table
6.
We were unable to locate the protocols for three
RCTs; therefore, we assessed the reporting bias by
means of comparing outcomes listed in the meth-ods
with the results, which indicated that the reported
results were approximately consistent with outcomes
listed in the methods.

Table 5. Grading of recommendations assessment, development, and evaluation system (GRADE) analysis: quality assessment of
clozapine for treatment-resistant bipolar disorder

Overall
Participants Risk of Large quality
d
Critical outcome (studies) bias Inconsistency Indirectness Imprecision Public bias effect of evidence

Open studies
a
CGI score 236 (5) Serious No No No Undetected No Very low
BPRS score 248 (5) No No No No Undetected No Low
YMRS score 47 (2) No No No No Undetected No Low
b
Social functioning 304 (4) Serious No No No Undetected No Very low
Hospital days/year 377 (2) No No No No Undetected No Low
Mean no. of admissions 377 (2) No No No No Undetected No Low
Randomized clinical trials
c
BPRS score 109 (2) No No No No Undetected No Moderate
c
HDRS score 109 (2) No No No No Undetected No Moderate

BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression; HDRS = Hamilton Depression Rating Scale; YMRS = Young
Mania Rating Scale.
a
Incomplete accounting of patients and outcome events.
b
Relatively few patients (n ≤ 10).
c
Lack of allocation concealment.
d
The quality of evidence was rated using the GRADE Working Group system. High quality indicates that further research is very
unlikely to change our confidence in the estimate of effect but none of the studies reached that level. Moderate quality indicates that
further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low
quality indi-cates that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely
to change the estimate. Very low quality indicates that we are very uncertain about the estimate.
 Clozapine for treatment-resistant bipolar disorder

Table 6. Clozapine adverse drug reactions in treatment-resistant

bipolar disorder

n (% of
Adverse drug reaction 797 total)

Blood cells Leukopenia 14 (1.7)

Decreases in white 6 (0.8)
blood cell count
Agranulocytosis 2 (0.3)
Metabolic system Weight gain 31 (4.0)
Weight loss 1 (0.1)
Hyperlipidemia 1 (0.1)
Increased appetite 1 (0.1)
Diabetes type 2 1 (0.1)
Endocrine system Sialorrhea 42 (5.2)
Sweating 4 (0.5)
Dry mouth 1 (0.1)
Influenza-like syndrome 1 (0.1)
Cardiovascular Abnormal EEG 6 (0.8)
system Orthostatic hypertension 6 (0.8)
Tachycardia 6 (0.8)
Orthostatic hypotension 2 (0.2)
Digestive system Constipation 40 (5.0)
Fig. 1. Preferred Reporting Items for Systematic Reviews and Diarrhea 8 (1.1)
Meta-Analyses (PRISMA) flow diagram. Nausea/vomiting 5 (0.6)
Postprandial regurgitation 1 (0.1)
Quality assessment of the included studies based Ileus 1 (0.1)
on the GRADE approach showed many limitations of Nervous system Sedation 98 (12.2)
Body ache and pain 15 (1.8)
the study designs, no obvious indi-rectness, Dizziness 11 (1.4)
imprecision in result reporting and large treatment Sleep cycle inversion 7 (1.1)
effect. Based on the above assessments, the quality of Transient fever 8 (0.9)
evidence presented for each outcome ranged from Urinary incontinence 6 (0.8)
‘very low’ to ‘moderate’ (Table 5). Seizure 4 (0.5)
Tremors 2 (0.2)
Fatigue 2 (0.2)
Clozapine RCTs for TRBD Neuroleptic malignant 1 (0.1)
syndrome
Our literature search yielded two clozapine RCTs for Bradykinesia 1 (0.1)
TRBD (Table 1). In these RCTs, adjunctive clozapine Enuresis 1 (0.1)
Mental confusion 1 (0.1)
treatment was superior to treatment as usual for
TRBD (45). In addition, clozapine with added lithium
was better than clozapine aug-mented with valproate
in rapid cycling BD (43). with schizophrenia and psychotic BD indicated that
the latter had significantly higher response rates to
clozapine (12).
Clozapine retrospective trials for TRBD

Three clozapine retrospective trials for TRBD were
identified (Table 2). Two trials described the num-ber
and duration of hospitalizations, the number of
psychotropic co-medications and the number of
hospital visits for medical reasons and for inten-tional
self-harm/overdose as significantly reduced during
clozapine treatment (12, 29, 51, 58). Another
retrospective study comparing patients
Clozapine open-label prospective trials for TRBD
The 10 clozapine open-label prospective studies for
TRBD (Table 3) included five long-term follow-up
studies (11, 16, 59–61), four focused on mania (44,
62–64) and one focused on adolescent patients (65).
The studies found that patients on clozapine
demonstrated a significant decrease in the Young
Mania Rating Scale (YMRS), Hamilton Depres-sion
Rating Scale (HDRS), Brief Psychiatric Rat-ing Scale
(BPRS), and Clinical Global Impression Scale (CGI)
scores (44, 66); the presence of suicidal ideation and
aggressive behavior at intake pre-dicted greater
improvement at endpoint (59, 65) and improvement
in social functioning (16). In

Li et al.
addition, they also found that BD patients showed
greater clinical improvement than those with
schizophrenia in the long-term follow-up (11, 60).
Clozapine ADRs in TRBD
ADRs are summarized in Table 6. The prevalences of
the most serious ADRs were leukopenia, 2%;
agranulocytosis, 0.3%; and seizure, 0.5%. There were
no cases of myocarditis. The most frequent clinically
significant ADRs were sedation (12%), constipation
(5%), sialorrhea (5%), weight gain (4%), and any
kind of pain (2%). Other ADRs with a frequency of
0.5–1.0% were dizziness, diar-rhea (1%), transient
fever, urinary incontinence, abnormal EEG,
tachycardia, orthostatic hyperten-sion, and nausea.
Other ADRs are described in Table 6.
Discussion
This is the first systematic review of clozapine for
TRBD summarizing its efficacy and safety. Our
comprehensive systematic review included 15 stud-
ies with a total of 1,044 patients and suggests that
clozapine may be an effective therapy, safe and well
tolerated. Although we excluded all of the case series
and case reports in this comprehensive review, the
literature search provided 13 case reports/series in
which clozapine was used for TRBD (Table 4). The
13 articles included five on mania (42, 70–73), five
on rapid cycling BD (15, 74–77), and three on other
TRBDs (29, 78, 79). Overall, almost all cases were
treatment-resistant and had a remission after
switching to clozapine monotherapy or adding
clozapine to other drugs.
Strengths of the study
While many patients with BD respond well to con-
ventional medications (including antidepressants,
mood stabilizers and antipsychotics), a substantial
proportion do not achieve a satisfactory response
(67–69). This systematic review showed that cloza-
pine may be an efficacious therapy for TRBD. First,
RCTs showed that: (i) clozapine add-on treatment
was superior to treatment as usual in mania, and (ii)
clozapine plus lithium was better than clozapine plus
valproate in rapid cycling BD. Secondly, retrospective
studies of clozapine for TRBD indicated that the total
number and dura-tion of hospitalizations and the
number of psycho-tropic co-medications were
significantly reduced during clozapine treatment.
Thirdly, in open-label prospective studies, patients
treated with clozapine demonstrated a significant
decrease in the YMRS,
HDRS, BPRS, and CGI scores, evidenced
improvement in social functioning, suicidal idea-tion
and aggressive behavior, and had fewer subse-quent
affective episodes; furthermore, patients with TRBD
showed greater clinical improvement than those with
schizophrenia in the long-term follow-up in these
trials. The current review also suggests that clozapine
may have anti-manic properties in some children and
adolescents with TRBD.
In general, this review found that clozapine for
TRBD was safe and well tolerated (Table 6). Seda-
tion, constipation, sialorrhea, weight gain, and pain
were the common ADRs, which is consistent with
schizophrenia studies (80, 81), and they were rather
mild and tolerable to most patients. Moder-ate ADRs
included dizziness, diarrhea, transient fever, urinary
incontinence, abnormal EEG, tachy-cardia,
orthostatic hypertension, and nausea. Rare ADRs
were sweating, hyperlipidemia, diabetes type 2,
influenza-like syndrome, postprandial regurgitation,
ileus, and bradykinesia, which is also comparable
with schizophrenia studies (80, 82). These ADRs
were not severe enough to result in drug
discontinuation. The ADRs in the metabolic system
were obviously low; there is the possibility of a major
underreport in the included trials.
Among all the reports, 17 patients had leukope-nia
(2%), two had agranulocytosis (0.2%), and five had
seizures (0.5%). These figures tend to be lower than
averages reported in schizophrenia reviews (83–89).
We are not sure whether the lower ADR frequency in
BD versus schizophrenia trials is real or an artefact.
Greater underreport and different methodologies may
contribute to an artificially low ADR frequency. Some
clozapine ADRs are dose-related; others are not.
Doses in BD trials appear lower than doses in
Western schizophrenia studies, but it was not possible
to control doses for con-founders such as smoking
[which induced cloza-pine metabolism probably by
inducing the cytochrome P450 1A2 (CYP1A2)] and
racial differ-ences (see the discussion in the section
‘Limitations of the study’ below) (64, 87, 89). The
agranulocyto-sis risk is still a concern for clinicians,
but manda-tory blood monitoring has been shown to
considerably reduce the incidence of fully devel-oped
cases of agranulocytosis (80). Thus, appropri-ate
management of clozapine ADRs facilitates
maximization of the benefits of clozapine treat-ment,
and physicians and patients alike should be aware that
there are a range of benefits to cloza-pine use that
outweigh its risk (80, 90, 91).
Clozapine treatment was associated with signifi-
cant improvement in tardive dyskinesia in seven
patients (92–94); clozapine may be useful for long-
term treatment to lower tardive dyskinesia risk (93,

95, 96). Furthermore, once tardive dyskinesia or
dystonia is established, clozapine may be useful for
both control of the movement disorder and BD (93,
96).
The main strength of this study is that we also
searched Chinese databases in the systematic review,
which included all TRBD clozapine trials conducted
in China, where clozapine is widely used. Thus, it is
the first review to include all trials available without
applying any language restric-tions. We found RCTs
of clozapine monotherapy or clozapine combined
with other medications ver-sus other treatments in
patients with TRBD; the comparison treatments
included a mood stabilizer (97, 98), other
antipsychotics (99–102), clozapine plus a mood
stabilizer versus a mood stabilizer (97, 103, 104), and
clozapine plus a mood stabilizer ver-sus other
antipsychotics plus a mood stabilizer (103–109) in
the treatment of BD in China. We also found two
RCTs, one open-label prospective study, and two case
reports on the use of clozapine for TRBD in the
Chinese literature, including the only placebo-
controlled clozapine RCT for TRMD (41).
Limitations of the study
A few limitations of the current review need to be
acknowledged. First, it was not possible to conduct a
meta-analysis because of the study’s heterogene-ity,
including differences in illness phase (mania,
depression or rapid cycling BD), methodology (open-
label trials or RCTs) and outcome definition
(response or remission). This great heterogeneity may
violate basic statistical assumptions and make these
analyses error-prone. Therefore, we only extracted
data onto standard, simple forms on a case-by-case
basis and reported the efficacy of clozapine for
TRBD when available. Compared with data on
efficacy, there was lower heterogene-ity with ADR
data, and therefore data synthesis using ADRs was
conducted and the percentage of each ADR was
computed (Table 6).
Secondly, most of the clinical trials included here
had major methodological problems. Although this
review included 15 clinical trials, most of them were
open-label observational trials; only two RCTs were
available. There were no obvious reporting biases in
the RCTs, but reporting biases in other studies are
possible. Furthermore, the GRADE approach showed
that the quality of the evidence was ‘very low’ in CGI
score and psycho-social function; other outcomes
were from ‘low’ to ‘moderate’ (Table 5). Therefore,
the current review provided limited evidence
supporting clozapine use. However, two strengths of
the current review
Clozapine for treatment-resistant bipolar disorder
also need to be mentioned: (i) all available trials were
included, without applying any language restrictions;
and (ii) the efficacy case-by-case analysis and
computation of the percentage of each ADR provided
some evidence supporting the use of clozapine (Table
6).
Thirdly, some trials were ‘contaminated’ by some
patients with a diagnosis of schizoaffective disorder
or schizophrenia, which does not corre-spond to the
population described as the target population of
interest (those with TRBD). In some trials, we could
not separate patients with TRBD from the patients
with schizoaffective disorder or schizophrenia, but
the tables provide details of these ‘contaminated’
studies.
A fourth limitation of this review and all the studies
reviewed in it is the lack of close attention to issues
regarding clozapine pharmacokinetics and dosing.
Clozapine dosing is influenced by racial differences,
drug–drug interactions and smoking. In 1997, it was
already reported that Chi-nese patients tended to
receive approximately half of the clozapine dosage
used in Western counties (110, 111) but appeared to
have roughly similar clozapine levels, which is
indicative of lower cloza-pine metabolism in Chinese
patients. The literature has not stressed this difference
nor provided an explanation. Sirot et al. (112) carried
out a very important study that has not received
enough attention in the literature. They described
cyto-chrome P450 2C19 (CYP2C19) poor
metabolizers (PMs) as having 2.3-fold higher plasma
clozapine concentrations than patients with other
CYP2C19 genotypes. Approximately 25% of the
Chinese population are CYP2C19 PMs.
Studies of adjunctive clozapine treatment in TRBD
usually ignore the major differences in clozapine
metabolism associated with co-med-ication.
Carbamazepine is a major inducer of clozapine
metabolism (113) and it is possible that valproate may
be a mild inducer (114). Fluvox-amine is a major
inhibitor of clozapine metabolism
(115) and paroxetine and fluoxetine are mild inhib-
itors (114, 115).
In conclusion, future studies and meta-analyses of
clozapine for TRBD will need to pay attention to
important pharmacokinetic differences associ-ated
with racial differences, co-medication and smoking,
which may have major influences on clozapine
dosing but at present are ignored in most published
articles.
Comparison with other studies
Poon et al. (17) performed a literature review on
TRBD research findings. It provided few promising
Li et al.
leads other than the use of clozapine for TRBD
mania, which is comparable to our analysis. Their
review was limited by: (i) inclusion of only two
clozapine trials (44, 45), (ii) lack of report on cloza-
pine ADRs, and (iii) lack of inclusion of Chinese
studies which include larger numbers of patients.
Gitlin (116) conducted a review on this topic. That
review indicated that combining multiple agents was
the most commonly used clinical strat-egy for TRBD;
an approach that may be effective for treatment-
resistant patients included high-dose thyroid
augmentation, clozapine, calcium channel blockers,
and electroconvulsive therapy, which is consistent
with our findings. However, only three studies of
clozapine treatment were included (45, 60, 64), and
none of the Chinese studies were included. Similarly,
there was no safety analysis or data synthesis.
Frye et al. (117) reviewed the use of atypical
antipsychotics in the treatment of BD, focusing on
clozapine as the prototypical agent. That review
indicated that the early clinical experience of
clozapine as a potential mood stabilizer sug-gested
greater anti-manic than antidepressant properties.
However, that review only included some trials
conducted before 1998, which excluded most trials of
clozapine for TRBD. Similarly, there was no safety
analysis or data synthesis in that analysis.
Conclusions
TRBD is a complex, often severe and disabling
psychiatric disorder and it often poses a thera-peutic
challenge (17, 118). This systematic review shows
that clozapine monotherapy or its combi-nation with
other medications for TRBD may be both safe and
effective. Long-term use of cloza-pine appeared to be
associated with improvement in clinical symptoms,
measurable social and functional gains, and decreased
hospitalization. Constipation, sedation, sialorrhea,
weight gain, aches and pain were the most commonly
reported ADRs, though none were severe enough to
result in drug discontinuation. The percent-ages of
patients with leukocytopenia, agranulocy-tosis and
seizure were lower than in studies of clozapine for
schizophrenia, but the possibility cannot be ruled out
that they may be contami-nated by ADR
underreporting. Clozapine for TRBD may increase
treatment compliance, which may offer additional
therapeutic benefits. On the other hand, some patients
may have poor adherence or may not be willing to
start cloza-pine treatment due to the blood collections
required for the prevention of agranulocytosis.
This comprehensive review has focused on TRBD,
but future reviews need to focus on the role of
clozapine for the treatment of BD in general. Though
clozapine is rarely used for non-treatment-resistant
BD elsewhere in the world, emerging evidence from
China is encour-aging (41, 97, 98). Since the early
1980s, few clozapine RCTs for BD in general have
been published; once more clozapine RCTs have been
published, a meta-analysis of non-treatment resistant
BD, if supportive of clozapine use, will provide
clinicians with more choices.
Acknowledgements
The authors thank Lorraine Maw, M.A., for editorial assis-tance.
This study was supported by the Beijing Science and Technology
Commission (grant D121100005012002). No com-mercial
organizations had any role in the writing of this paper for
publication.
Disclosures
The authors of this paper report no financial relationship with
commercial interests within the last three years.
Author contributions
X-BL and Y-LT contributed equally to the review of the arti-cles
and to the writing of the first draft. C-YW and JdL con-tributed by
improving the first and later drafts. All authors contributed to and
approved the final manuscript.
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